This research establishes the instrumental control of ion-selective electrodes as an alternative measurement principle to traditional zero current potentiometry. While ion-selective electrodes are routine tools in clinical laboratories all over the world, numerous new sensing principles that have recently been developed for ISEs make use of ion fluxes, for which classical potentiometry is no longer an adequate transduction method. It is proposed to apply repetitive current and potential pulses to ion-selective membranes that are designed to lack ion-exchanger properties. The resulting sensor responses have the same look and feel as in zero current potentiometry and will be comprehensively compared to each other. As an initial important application of this method, fully reversible polyion sensors for the detection of the anticoagulant heparin and its antidote protamine will be developed. For this first time, this methodology forms the foundation for a truly continuous monitoring technology for these important analytes in whole blood samples during surgery. In addition, the interrogation technique will be optimized and applied to numerous other cases where zero current potentiometry has shown, or is expected to show, unsatisfactory sensor behavior.